Brodmerkel Carrie M, Huber Reid, Covington Maryanne, Diamond Sharon, Hall Leslie, Collins Robert, Leffet Lynn, Gallagher Karen, Feldman Patricia, Collier Paul, Stow Mark, Gu Xiaomei, Baribaud Frederic, Shin Niu, Thomas Beth, Burn Tim, Hollis Greg, Yeleswaram Swamy, Solomon Kim, Friedman Steve, Wang Anlai, Xue Chu Biao, Newton Robert C, Scherle Peggy, Vaddi Kris
Incyte Corporation, Wilmington, DE 19880, USA.
J Immunol. 2005 Oct 15;175(8):5370-8. doi: 10.4049/jimmunol.175.8.5370.
This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.
本报告描述了INCB3344的特性，它是一种新型、强效且具有选择性的小鼠CCR2受体小分子拮抗剂。迄今为止发现的小分子CCR2拮抗剂缺乏固有的啮齿动物交叉反应性，这妨碍了对该受体拮抗剂及其治疗相关性的药理学研究。在体外，INCB3344以纳摩尔效力（IC(50)=10 nM）抑制CCL2与小鼠单核细胞的结合，并以相似效力对CCL2介导的功能反应（如ERK磷酸化和趋化性）表现出剂量依赖性抑制。针对包括其他CC趋化因子受体在内的一组G蛋白偶联受体，INCB3344对CCR2的选择性至少高100倍。INCB3344在啮齿动物中具有良好的口服生物利用度和全身暴露性，这使得能够进行体内药理学研究。在迟发型超敏反应小鼠模型中，INCB3344治疗导致巨噬细胞流入的剂量依赖性抑制。迟发型超敏反应模型组织的组织病理学分析表明，抑制CCR2会导致组织炎症大幅减少，这表明巨噬细胞在基于免疫的炎症反应中起协调作用。这些结果促使对INCB3344在炎症性疾病模型中的研究。我们证明，对实验性自身免疫性脑脊髓炎（一种多发性硬化症模型）以及炎症性关节炎大鼠模型的小鼠给予治疗剂量的INCB3344可显著减轻疾病。总之，我们首次报告了一种选择性、强效且对啮齿动物有活性的小分子CCR2拮抗剂的药理学特性。这些数据支持将该受体作为慢性炎症性疾病治疗的靶点。
